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MTHFR 677C>T effects on anterior cingulate structure and function during response monitoring in schizophrenia: a preliminary study

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Abstract

Patients with schizophrenia exhibit deficient response monitoring as indexed by blunted activation of the dorsal anterior cingulate cortex (dACC) and functionally related regions during error commission. This pattern may reflect heritable alterations of dACC function. We examined whether the hypofunctional 677C>T variant in MTHFR, a candidate schizophrenia risk gene, contributed to our previous findings of blunted error-related dACC activation and reduced microstructural integrity of dACC white matter. Eighteen medicated outpatients with schizophrenia underwent diffusion tensor imaging and performed an antisaccade paradigm during functional magnetic resonance imaging (fMRI). T allele carriers exhibited significantly less error-related activation than C/C patients in bilateral dACC and substantia nigra, regions that are thought to mediate dopamine-dependent error-based reinforcement learning. T carrier patients also showed significantly lower fractional anisotropy in bilateral dACC. These findings suggest that the MTHFR 677T allele blunts response monitoring in schizophrenia, presumably via effects on dopamine signaling and dACC white matter microstructural integrity.

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Acknowledgements and conflict of interest

This work was supported by the National Institute for Mental Health (R01 MH67720) and NARSAD Independent Investigator Award (to DSM); the Charles A. King Trust, Bank of America, Co-Trustee and the Bushrod H. Campbell and Adah F. Hall Charity Fund, Alden Trust, and Howard Hughes Medical Institute Physician Scientist Early Career Award (to JLR); the Mental Illness Neuroscience Discovery (MIND) Institute (DOE DE-FG02-99ER62764); and the National Center for Research Resources (P41RR14075). We thank Doug Greve for helpful discussions regarding the manuscript. None of the authors report any conflicts of interest. In memory of Jesse Friedman.

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Authors and Affiliations

  1. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA

    Joshua L. Roffman, David G. Brohawn, Jesse S. Friedman, Kara A. Dyckman, Katharine N. Thakkar, Yigal Agam, Donald C. Goff & Dara S. Manoach

  2. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA

    Mark G. Vangel

  3. Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, 02129, USA

    Mark G. Vangel & Dara S. Manoach

  4. Massachusetts General Hospital, 149 13th St, Room 2606, Charlestown, MA, 02129, USA

    Joshua L. Roffman

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  1. Joshua L. Roffman
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Correspondence to Joshua L. Roffman.

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Jesse S. Friedman: Deceased

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Supplemental Figure 1

Schematic depiction of the saccadic paradigm with idealized eye position traces. Saccadic trials lasted 4000 ms and began with an instructional cue at the center of the screen. For half of the participants, orange concentric rings were the cue for a prosaccade trial (a) and a blue “X” was the cue for an antisaccade trial (b). These cues were reversed for the rest of the participants. The cue was flanked horizontally by two small green squares of 0.2° width that marked the potential locations of stimulus appearance, 10° left and right of center. These squares remained on the screen for the duration of each run. (c) At 300 ms, the instructional cue was replaced by a green fixation ring at the center of the screen, of 0.4° diameter and luminance of 20 cd/m2. After 1700 ms, the ring shifted to one of the two target locations, right or left, with equal probability. This was the stimulus to which the participant responded by either making a saccade to it (prosaccade) or to the square on the opposite side (antisaccade). The green ring remained in the peripheral location for 1000 ms and then returned to the center, where participants were also to return their gaze for 1000 ms before the start of the next trial. Fixation intervals were simply a continuation of the fixation display that constituted the final second of the previous saccadic trial. (JPEG 192 kb)

Supplemental Figure 2

Statistical maps of MTHFR 677C>T genotype effects in the contrast of antisaccade correct versus fixation at 4 s displayed on the inflated medial and lateral cortical surfaces. The dACC is outlined in green. (JPEG 309 kb)

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Roffman, J.L., Brohawn, D.G., Friedman, J.S. et al. MTHFR 677C>T effects on anterior cingulate structure and function during response monitoring in schizophrenia: a preliminary study. Brain Imaging and Behavior 5, 65–75 (2011). https://doi.org/10.1007/s11682-010-9111-2

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